Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.

The hydrolytic degradation of squaramides and squaramic acids, the product of partial hydrolysis of squaramides, has been evaluated by UV spectroscopy at 37 °C in the pH range 3-10. Under these conditions, the compounds are kinetically stable over long time periods (>100 days). At pH >10, the hydrolysis of the squaramate anions shows first-order dependence on both squaramate and OH. At the same temperature and [OH], the hydrolysis of squaramides usually displays biphasic spectral changes (A → B → C kinetic model) with formation of squaramates as detectable reaction intermediates. The measured rates for the first step (k ≈ 10 M s) are 2-3 orders of magnitude faster than those for the second step (k ≈ 10 M s). Experiments at different temperatures provide activation parameters with values of ΔH ≈ 9-18 kcal mol and ΔS ≈ -5 to -30 cal K mol. DFT calculations show that the mechanism for the alkaline hydrolysis of squaramic acids is quite similar to that of amides.

The importance of a synergic combination between electrostatic and hydrogen‐bonding interactions has been demonstrated. A self‐complementary amidosquarate‐squaramide host for miltefosine has been disclosed. In DMSO, this rather structurally simple host exhibits high affinity and enhanced selectivity for miltefosine owing to the goal‐keeping effect of the amidosquarate unit.

In the presence of Ag(I), the monoanion of a cyano-N-squaraine (I) generates an intense fluorescent turn-on response. Experimental evidence and DFT calculations reveal a sequence of deprotonation-coordination events in which...